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naked cuticle encodes an inducible antagonist of Wnt signalling

Nature volume 403, pages 789–795 (2000)Cite this article

Abstract

During animal development, cells have to respond appropriately to localized secreted signals. Proper responses to Hedgehog, transforming growth factor-β, epidermal growth factor and fibroblast growth factor/Ras signals require cognate inducible antagonists such as Patched, Dad, Argos and Sprouty1. Wnt signals are crucial in development and neoplasia2. Here we show that naked cuticle (nkd), a Drosophila segment-polarity gene, encodes an inducible antagonist for the Wnt signal Wingless (Wg). In fly embryos and imaginal discs nkd transcription is induced by Wg. In embryos, decreased nkd function has an effect similar to excess Wg; at later stages such a decrease appears to have no effect. Conversely, overproduction of Nkd in Drosophila and misexpression of Nkd in the vertebrate Xenopus laevis result in phenotypes resembling those of loss of Wg/Wnt function. nkd encodes a protein with a single EF hand (a calcium-binding motif) that is most similar to the recoverin family of myristoyl switch proteins. Nkd may therefore link ion fluxes to the regulation of the potency, duration or distribution of Wnt signals. Signal-inducible feedback antagonists such as nkd may limit the effects of Wnt proteins in development and disease.

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Figure 1: nkd embryonic phenotype and rescue by nkd cDNA.
Figure 2: The nkd gene.
Figure 3: nkd expression and dependence on wg. a, nkd expression during embryonic stages 6–7 (left), 9 (middle) and 11 (right); anterior is left in all panels.
Figure 4: Consequences of altered nkd activity.
Figure 5: Misexpression of fly Nkd in Xenopus embryos and animal caps.

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References

  1. Perrimon, N. & McMahon, A. P. Negative feedback mechanisms and their roles during pattern formation Cell 97, 13–16 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Cadigan, K. M. & Nusse, R. Wnt signaling: a common theme in animal development Genes Dev. 11, 3286– 3305 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. DiNardo, S., Heemskerk, J., Dougan, S. & O'Farrell, P. H. The making of a maggot: patterning the Drosophila embryonic epidermis Curr. Opin. Genet. Dev. 4, 529–534 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bejsovec, A. & Martinez Arias, A. Roles of wingless in patterning the larval epidermis of Drosophila Development 113, 471–485 ( 1991).

    CAS  PubMed  Google Scholar 

  5. Sanson, B., Alexandre, C., Fascetti, N. & Vincent, J. P. Engrailed and hedgehog make the range of Wingless asymmetric in Drosophila embryos Cell 98, 207– 216 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Jürgens, G., Wieschaus, E., Nüsslein-Volhard, C. & Kluding, H. Mutations affecting the pattern of the larval cuticle in Drosophila melanogaster . II. Zygotic loci on the third chromosome Wilhelm Roux Arch. Dev. Biol. 193, 283–295 (1984).

    Article  Google Scholar 

  7. Noordermeer, J., Johnston, P., Rijsewijk, F., Nusse, R. & Lawrence, P. A. The consequences of ubiquitous expression of the wingless gene in the Drosophila embryo Development 116, 711–719 (1992).

    CAS  PubMed  Google Scholar 

  8. Siegfried, E., Chou, T. B. & Perrimon, N. wingless signaling acts through zeste-white 3, the Drosophila homolog of glycogen synthase kinase-3, to regulate engrailed and establish cell fate Cell 71, 1167–1179 (1992).

    Article  CAS  PubMed  Google Scholar 

  9. Hamada, F. et al. Negative regulation of Wingless signaling by D-axin, a Drosophila homolog of axin Science 283, 1739– 1742 (1999).

    Article  CAS  ADS  PubMed  Google Scholar 

  10. McCartney, B. M. et al. Drosophila APC2 is a cytoskeletally-associated protein that regulates wingless signaling in the embryonic epidermis J. Cell Biol. 146, 1303–1318 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bejsovec, A. & Wieschaus, E. Segment polarity gene interactions modulate epidermal patterning in Drosophila embryos Development 119, 501–517 ( 1993).

    CAS  PubMed  Google Scholar 

  12. Dougan, S. & DiNardo, S. Drosophila wingless generates cell type diversity among engrailed expressing cells Nature 360, 347–350 ( 1992).

    Article  CAS  ADS  PubMed  Google Scholar 

  13. Pazdera, T. M., Janardhan, P. & Minden, J. S. Patterned epidermal cell death in wild-type and segment polarity mutant Drosophila embryos Development 125, 3427–3436 (1998).

    CAS  PubMed  Google Scholar 

  14. Moline, M. M., Southern, C. & Bejsovec, A. Directionality of Wingless protein transport influences epidermal patterning in the Drosophila embryo Development 126, 4375–4384 ( 1999).

    CAS  PubMed  Google Scholar 

  15. Pai, L. M., Orsulic, S., Bejsovec, A. & Peifer, M. Negative regulation of Armadillo, a Wingless effector in Drosophila Development 124, 2255–2266 ( 1997).

    CAS  PubMed  Google Scholar 

  16. Steitz, M. C., Wickenheisser, J. K. & Siegfried, E. Overexpression of zeste white 3 blocks wingless signaling in the Drosophila embryonic midgut Dev. Biol. 197, 218–233 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  17. Brand, A. H. & Perrimon, N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes Development 118, 401–415 ( 1993).

    CAS  PubMed  Google Scholar 

  18. Baker, N. E. Transcription of the segment-polarity gene wingless in the imaginal discs of Drosophila, and the phenotype of a pupal-lethal wingless mutation Development 102, 489–497 (1988).

    CAS  PubMed  Google Scholar 

  19. Couso, J. P., Bate, M. & Martinez-Arias, A. A wingless-dependent polar coordinate system in Drosophila imaginal discs Science 259, 484–489 (1993).

    Article  CAS  ADS  PubMed  Google Scholar 

  20. Shirras, A. D. & Couso, J. P. Cell fates in the adult abdomen of Drosophila are determined by wingless during pupal development Dev. Biol. 175, 24–36 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Ma, C. & Moses, K. Wingless and patched are negative regulators of the morphogenetic furrow and can affect tissue polarity in the developing Drosophila compound eye Development 121, 2279–2289 ( 1995).

    CAS  PubMed  Google Scholar 

  22. Couso, J. P., Bishop, S. A. & Martinez Arias, A. The wingless signalling pathway and the patterning of the wing margin in Drosophila Development 120, 621–636 (1994).

    CAS  PubMed  Google Scholar 

  23. Brook, W. J. & Cohen, S. M. Antagonistic interactions between wingless and decapentaplegic responsible for dorsal-ventral pattern in the Drosophila leg Science 273, 1373–1377 (1996).

    Article  CAS  ADS  PubMed  Google Scholar 

  24. Moon, R. T., Brown, J. D., Yang-Snyder, J. A. & Miller, J. R. Structurally related receptors and antagonists compete for secreted Wnt ligands Cell 88, 725–728 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Deardorff, M. A., Tan, C., Conrad, L. J. & Klein, P. S. Frizzled-8 is expressed in the Spemann organizer and plays a role in early morphogenesis Development 125, 2687– 2700 (1998).

    CAS  PubMed  Google Scholar 

  26. Itoh, K. & Sokol, S. Y. Axis determination by inhibition of Wnt signaling in Xenopus Genes Dev. 13, 2328–2336 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sokol, S. Y. Analysis of Dishevelled signalling pathways during Xenopus development Curr. Biol. 6, 1456–1467 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Hoppler, S., Brown, J. D. & Moon, R. T. Expression of a dominant-negative Wnt blocks induction of MyoD in Xenopus embryos Genes Dev. 10, 2805–2817 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. Glinka, A., Wu, W., Onichtchouk, D., Blumenstock, C. & Niehrs, C. Head induction by simultaneous repression of Bmp and Wnt signalling in Xenopus Nature 389, 517–519 (1997).

    Article  CAS  ADS  PubMed  Google Scholar 

  30. Flaherty, K. M., Zozulya, S., Stryer, L. & McKay, D. B. Three-dimensional structure of recoverin, a calcium sensor in vision Cell 75, 709–716 (1993).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank L. Mathies for identifying the P element in the nkd gene; D. Bilder, K. Cadigan, S. Carroll, C. Goodman, A. Hudson, N. Ito, C. Kirkpatrick, A. Martinez-Arias, R. Nusse, C. Nüsslein-Volhard, G. Panganaban, N. Patel, M. Peifer, N. Perrimon, G. Rubin and A. Spradling for mutants, reagents and advice; J. Axelrod, L. Luo, R. Nusse and R. Rousset for comments on the manuscript; S. Blair, S. Conley, S. DiNardo, A. Martinez-Arias, S. Sokol and M. Deardorff for providing information before publication; M. Fish for injection of UAS–Nkd constructs; and K. Cadigan and D. Bilder for stained material. W.Z. and J.M. were supported by postdoctoral training grants from the NIH and by the Howard Hughes Medical Institute (HHMI). K.A.W. was supported by an HHMI postdoctoral fellowship for physicians and a NIH K-08 Award. P.K. and M.P.S. are Investigators of the HHMI.

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Author notes

  1. Wenlin Zeng, Keith A. Wharton and Judith A. Mack: These three authors contributed equally to this work

Authors and Affiliations

  1. Departments of Developmental Biology, Howard Hughes Medical Institute, Beckman Center B300, Stanford University School of Medicine, 279 Campus Drive, Stanford, 94305, California, USA

    Wenlin Zeng, Keith A. Wharton Jr, Judith A. Mack, Kevin Wang, Matthew Gadbaw, Kaye Suyama & Matthew P. Scott

  2. Departments of Genetics, Howard Hughes Medical Institute, Beckman Center B300, Stanford University School of Medicine, 279 Campus Drive, Stanford, 94305, California, USA

    Wenlin Zeng, Keith A. Wharton Jr, Judith A. Mack, Kevin Wang, Matthew Gadbaw, Kaye Suyama & Matthew P. Scott

  3. Departments of Pathology, Howard Hughes Medical Institute, Beckman Center B300, Stanford University School of Medicine, 279 Campus Drive, Stanford, 94305, California, USA

    Keith A. Wharton Jr

  4. Department of Internal Medicine, Howard Hughes Medical Institute University of Pennsylvania School of Medicine, Clinical Research Building Room 405, 415 Curie Boulevard, Philadelphia, 19104-6148, Pennsylvania, USA

    Peter S. Klein

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Correspondence to Matthew P. Scott.

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Zeng, W., Wharton, K., Mack, J. et al. naked cuticle encodes an inducible antagonist of Wnt signalling . Nature 403, 789–795 (2000). https://doi.org/10.1038/35001615

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